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Bordetella Pertussis Colonisation Challenge Study (Periscope)

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ClinicalTrials.gov Identifier: NCT03751514
Recruitment Status : Recruiting
First Posted : November 23, 2018
Last Update Posted : February 27, 2020
Sponsor:
Collaborators:
Public Health England
University Hospital Southampton NHS Foundation Trust
Information provided by (Responsible Party):
University of Southampton

Brief Summary:
This is a prospective controlled human challenge study consisting of two phases; Phase A: Development of a B. pertussis human challenge model; pilot to establish the standard inoculum Phase B: Development of a modified B. pertussis human challenge model

Condition or disease Intervention/treatment Phase
Whooping Cough Biological: Bordetella Pertussis B1917 Drug: Azithromycin 500 mg Other: Sterile Saline Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: Human challenge study
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Human Controlled Infection Study to Establish a Safe, Reproducible and Practical Human Bordetella Pertussis Colonisation Model for the Identification of Correlates of Protection Against Colonisation (BPCCS)
Actual Study Start Date : May 22, 2017
Estimated Primary Completion Date : February 2, 2021
Estimated Study Completion Date : February 2, 2021


Arm Intervention/treatment
Experimental: Phase A - SI

Phase A aims to determine a 'standard inoculum' dose (SI), which results in safe colonisation of 70% of volunteers.

The SI will be identified in a dose escalating or de-escalating experiment commencing at 10-3 colony forming units B. pertussis administered intranasally. Each group of volunteers will be inoculated at half log-fold increasing/decreasing doses until the endpoint is reached. The experiment will be continued until the SI yields 10 subjects who are colonised at day 14.

Intervention to be administered: Bordetella Pertussis B1917

Biological: Bordetella Pertussis B1917

The B. pertussis isolate to be used in this human colonisation model is strain B1917, which is representative of current isolates in Europe. The strain, isolated in 2000 from a Dutch patient with B. pertussis disease, expresses Prn, PT and Filamentous Haemagglutinin (FHA). This strain has been extensively characterised in the mouse model as well as by proteomics and transcriptomics and has a closed genome available. It is fully sensitive to azithromycin in vitro.

Providing there are no safety concerns the standard inoculum (SI) will be identified in a dose escalating or de-escalating experiment commencing at 103 colony forming units administered intranasally.

Other Name: Whooping cough bacteria

Drug: Azithromycin 500 mg
To ameliorate risk of transmission of B. pertussis B1917 to the environment and household contacts, Azithromycin 500 mg once a day for 3 days will be given to eradicate colonisation with B. pertussis. The inoculum strain is fully sensitive to this antibiotic. Previous studies show that azithromycin eradicates colonisation in 97% of people in 48 hours.
Other Name: Zithromax

Experimental: Phase B Inoculum

Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence. The final protocol for phase B will be presented as a protocol amendment, it will be based on the SI and colonisation period identified in Phase A.

The SI determined in phase A will be used for all volunteers and eradication therapy will be given after the colonisation period based on the data of phase A. Approximately 30 individuals will receive the intranasal SI and will be treated with azithromycin for three days at the end of the colonisation period.

Intervention to be administered: Bordetella Pertussis B1917

Biological: Bordetella Pertussis B1917

The B. pertussis isolate to be used in this human colonisation model is strain B1917, which is representative of current isolates in Europe. The strain, isolated in 2000 from a Dutch patient with B. pertussis disease, expresses Prn, PT and Filamentous Haemagglutinin (FHA). This strain has been extensively characterised in the mouse model as well as by proteomics and transcriptomics and has a closed genome available. It is fully sensitive to azithromycin in vitro.

Providing there are no safety concerns the standard inoculum (SI) will be identified in a dose escalating or de-escalating experiment commencing at 103 colony forming units administered intranasally.

Other Name: Whooping cough bacteria

Drug: Azithromycin 500 mg
To ameliorate risk of transmission of B. pertussis B1917 to the environment and household contacts, Azithromycin 500 mg once a day for 3 days will be given to eradicate colonisation with B. pertussis. The inoculum strain is fully sensitive to this antibiotic. Previous studies show that azithromycin eradicates colonisation in 97% of people in 48 hours.
Other Name: Zithromax

Experimental: Phase B Sham

Phase B, using study data from phase A, will be used to design a more practical model - if possible conducted partially in an outpatient setting, which will be conditional on safety and transmission evidence.

Approximately 15 individuals will not receive the Bordetella Pertussis B1917, instead they will be given an intranasal sham of sterile saline and will be treated with azithromycin 500mg for three days at the end of the 'colonisation' period.

Drug: Azithromycin 500 mg
To ameliorate risk of transmission of B. pertussis B1917 to the environment and household contacts, Azithromycin 500 mg once a day for 3 days will be given to eradicate colonisation with B. pertussis. The inoculum strain is fully sensitive to this antibiotic. Previous studies show that azithromycin eradicates colonisation in 97% of people in 48 hours.
Other Name: Zithromax

Other: Sterile Saline
To compare against B. pertussis, some volunteers will be enrolled onto the Sham arm. These volunteers will not receive B. pertussis but instead be given sterile saline
Other Name: Sham




Primary Outcome Measures :
  1. Phase A - Inoculum Dose Determination [ Time Frame: Up to volunteer visit Day 14 ]
    The inoculum dose required to cause the safe colonisation of 70% of volunteers who are challenged. A starting inoculum of 10^3 bacteria will be used and incrementally increased until microbiologically proven Bp infection by positive culture of Bp from a nasopharyngeal swab (CFU/mL). Swabs are taken between time points day 0 and day 14 and compare with baseline.


Secondary Outcome Measures :
  1. Phase A and B - Immune Responses to exposure to Bordetella pertussis [ Time Frame: Up to volunteer visit Week 52 ]
    Measure the antibody response (IU/L) of volunteers who receive the inoculum against the immune responses of those that receive the sham treatment.

  2. Phase A - Accuracy of Inoculum Dosing Evaluation [ Time Frame: Up to volunteer visit Day 7 ]
    Measurement of the challenge dose (cfu/mL) actually given to volunteers by counting CFUs after culturing. This is done by culturing the remaining inoculum which has been given to the volunteers. Results are then compared with the prescribed dose (cfu/mL).

  3. Phase A and B - Number of participants with Bp exposure-related adverse events as assessed by study specific adverse event grading system based on CTCAE v4.0 [ Time Frame: Up to volunteer visit Day 365 ]
    After inoculation with Bordetella pertussis, participants will be admitted in the research unit to monitor adverse events closely.

  4. Phase A - Earliest Timepoint for Colonisation of the Nasopharynx [ Time Frame: Up to volunteer visit Day 14 ]
    The earliest day after inoculation at which colonisation of the nasopharynx (as detected by culture) is observed in 100% of those volunteers who subsequently seroconvert at day 28. Colonisation will be detected by positive culture of Bp from a nasopharyngeal swab taken between timepoints day 0 and 14

  5. Phase A and B - Bacterial Dynamics after Challenge [ Time Frame: Up to volunteer visit Day 14 ]
    Microbiological assays to detect and characterise Bp after challenge in nasopharyngeal swabs (culture and qPCR), nasal wash (culture including semi-quantitative method using cfu count/mL, and precision quantification with qPCR)and sequencing of isolates

  6. Phase A and B - Bacterial Dynamics after Challenge by culture [ Time Frame: Up to volunteer visit Day 14 ]
    Bp colonisation will be measured in nasopharyngeal swabs, nasal wash and throat swabs by culture using cfu count/mL

  7. Phase A and B - Bacterial Dynamics after Challenge by PCR [ Time Frame: Up to volunteer visit Day 14 ]
    Bp colonisation will be measured in nasopharyngeal swabs, nasal wash and throat swabs by culture using cfu count/mL

  8. Phase A - Environmental shedding of Bp [ Time Frame: Day 0-16 ]
    Air and mask samples will be collected of volunteers and cultured. Results will be expressed as cfu count

  9. Phase A & B - Immune Response in nasal wash to Challenge [ Time Frame: Up to volunteer visit Week 52 ]
    Immunological laboratory assays to measure innate, humoral, cell-mediated and mucosal responses to challenge in nasal washes.

  10. Phase A & B - Human Immune Response to Challenge in Saliva [ Time Frame: Up to volunteer visit Week 52 ]
    Antibody responses to challenge in saliva will be measured (Bp specific Immunoglobulin A (IgA) (IU/mL))

  11. Phase A & B - Correlation of qPCR results with Culture Results after Challenge [ Time Frame: Up to Day 16 ]
    Comparison of qPCR results with culture results after challenge: Microbiological assays in nasopharyngeal swabs and nasal washes (culture, qPCR) taken between day 0 and 16



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy adults aged 18 to 45 years inclusive on the day of screening
  • Fully conversant in the English language
  • Able to communicate easily by both mobile telephone and text messaging
  • Able and willing (in the investigator's opinion) to comply with all study requirements
  • Written informed consent to participate in the trial
  • Willingness to take a curative antibiotic regimen after inoculation with B. pertussis according to the study protocol
  • Agreement to be admitted to the National Institute for Health Research (NIHR)-Clinical research facility (CRF) Southampton for 17 days for phase A (from inoculation until two days after the eradication therapy is given) and for the duration necessary for phase B, depending on phase A results
  • Able to answer all questions on the informed consent quiz correctly

Exclusion Criteria:

  • Individuals who have inviolable commitments within 3 months of discharge from the inpatient phase of the study to make contact with:

    1. unimmunised or partially immunised children and infants aged < 1 year
    2. pregnant women >32 weeks who have not received pertussis vaccination at least a week prior to contact
  • Individuals who have household contacts working with

    1. unimmunised or partially immunised children and infants aged < 1 year
    2. pregnant women >32 weeks who have not received pertussis vaccination at least a week prior to contact
  • Phase A only: Volunteers will be excluded from this study if they have evidence of recent exposure to B. pertussis, as determined by anti-PT IgG ELISA (>20 IU/mL)
  • B. pertussis detected on nasopharyngeal swab taken before the challenge
  • Individuals who have a signs of a current infection at the time of inoculation with B. pertussis
  • Individuals who have participated in other interventional clinical trials in the last 12 weeks
  • Individuals who have a history of receiving B. pertussis vaccination in the last 5 years
  • Individuals who have a history of never being vaccinated against B. pertussis
  • Current smokers defined as having had a cigarette/cigar in the last week.
  • Use of systemic antibiotics within 30 days of or during the challenge
  • Any confirmed or suspected immunosuppressive or immune-deficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (topical steroids are allowed)
  • Use of immunoglobulins or blood products within 3 months prior to enrolment
  • History of allergic disease or reactions likely to be exacerbated by any component of the inoculum
  • Contraindications to the use of azithromycin or macrolides
  • Pregnancy, lactation or intention to become pregnant during the study
  • Any clinically significant abnormal finding on biochemistry, haematology, toxicology or serological blood tests, urinalysis or clinical examination - in the event of abnormal test results, confirmatory repeat tests will be requested
  • Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data, for example recent surgery to the nasopharynx

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03751514


Contacts
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Contact: Hans de Graaf, MRCPCH 02381204989 ext 4989 H.De-Graaf@soton.ac.uk

Locations
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United Kingdom
NIHR Wellcome Trust Clinical Research Facility, Southampton General Hospital Recruiting
Southampton, Hampshire, United Kingdom, SO16 6YD
Contact: Hans De Graaf, MRCPCH    02381204989 ext 4989    H.De-Graaf@soton.ac.uk   
Contact: Sara Hughes, MPhil    02381203853 ext 3853    Sara.Hughes@uhs.nhs.uk   
Principal Investigator: Robert C Read, MRCPMDFRCP         
Principal Investigator: Saul N Faust, FRCPCHFHEA         
Sub-Investigator: Hans de Graaf, MRCPCH         
Sponsors and Collaborators
University of Southampton
Public Health England
University Hospital Southampton NHS Foundation Trust
Investigators
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Principal Investigator: Robert C Read, MB MD FRCP University of Southampton
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Southampton
ClinicalTrials.gov Identifier: NCT03751514    
Other Study ID Numbers: RHM MED1396
17/SC/0006 ( Other Identifier: REC )
First Posted: November 23, 2018    Key Record Dates
Last Update Posted: February 27, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Southampton:
Bordetella Pertussis
Additional relevant MeSH terms:
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Whooping Cough
Bordetella Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Respiratory Tract Infections
Infection
Respiratory Tract Diseases
Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents